Reduction of av delay for treatment of cardiac disease

ABSTRACT

An implantable pacing device for delivering ventricular pacing may be configured to intermittently reduce the AVD interval for beneficial effect in patients with compromised ventricular function (e.g., HF patients and post-MI patients). The AVD interval may be reduced in an AVD reduction mode, by shortening the AVD in an atrial triggered ventricular pacing mode or by switching to a non-atrial triggered ventricular pacing mode (e.g., VVI) and delivering paces at a rate above the intrinsic rate. The physiological effects of AVD reduction may be either positive or negative on cardiac output, depending upon the individual patient.

RELATED APPLICATIONS

This application is a continuation-in-part of co-pending U.S. patentapplication Ser. No. 11/561,049, filed on Nov. 17, 2006 and 11/559,131,filed on Nov. 13, 2006, the disclosures of which are hereby incorporatedby reference.

FIELD OF THE INVENTION

This invention pertains to apparatus and methods for the treatment ofheart disease and to devices providing electrostimulation to the heartsuch as cardiac pacemakers.

BACKGROUND

Cardiac rhythm management devices are implantable devices that provideelectrical stimulation to selected chambers of the heart in order totreat disorders of cardiac rhythm and include pacemakers and implantablecardioverter/defibrillators. A pacemaker is a cardiac rhythm managementdevice that paces the heart with timed pacing pulses. (As the term isused herein, a pacemaker is any cardiac rhythm management device with apacing functionality, regardless of any other functions it may performsuch as delivery of cardioversion/defibrillation shocks.) The mostcommon condition for which pacemakers are used is in the treatment ofbradycardia, where the ventricular rate is too slow. Atrio-ventricularconduction defects (i.e., AV block) that are permanent or intermittentand sick sinus syndrome represent the most common causes of bradycardiafor which permanent pacing may be indicated. If functioning properly,the pacemaker makes up for the heart's inability to pace itself at anappropriate rhythm in order to meet metabolic demand by enforcing aminimum heart rate. Pacing therapy may also be applied in order to treatcardiac rhythms that are too fast, termed anti-tachycardia pacing.

Also included within the concept of cardiac rhythm is the manner anddegree to which the heart chambers contract during a cardiac cycle toresult in the efficient pumping of blood. For example, the heart pumpsmore effectively when the chambers contract in a coordinated manner. Theheart has specialized conduction pathways in both the atria and theventricles that enable the rapid conduction of excitation (i.e.,depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Patients who exhibit pathology of these conduction pathways,such as bundle branch blocks, can thus suffer compromised cardiacoutput. Heart failure (HF) refers to a clinical syndrome in which anabnormality of cardiac function causes a below normal cardiac outputthat can fall below a level adequate to meet the metabolic demand ofperipheral tissues. Heart failure can be due to a variety of etiologieswith ischemic heart disease being the most common (e.g., HF resultingfrom a myocardial infarction or MI). Intraventricular and/orinterventricular conduction defects are commonly found in HF patients.In order to treat these problems, cardiac rhythm management devices havebeen developed which provide electrical pacing stimulation to one ormore heart chambers in an attempt to improve the coordination of atrialand/or ventricular contractions, termed cardiac resynchronizationtherapy (CRT). Currently, a most common form of CRT is biventricularpacing in which paces are delivered to both ventricles in a manner thatsynchronizes their contractions.

Bradycardia pacing and CRT are delivered using bradycardia pacing modesthat determine how the pacing pulses are delivered in response to sensedcardiac events and lapsed time intervals. Such modes may either besingle-chamber pacing, where either an atrium or a ventricle is paced,or dual-chamber pacing in which both an atrium and a ventricle arepaced. Particular modes may be designated by a letter code of threepositions where each letter in the code refers to a specific function ofthe pacemaker. The first letter refers to which heart chambers are pacedand which may be an A (for atrium), a V (for ventricle), D (for bothchambers), or O (for none). (As the code is used herein, when an atriumor ventricle designated as paced, this may also refer to multiple sitepacing such as biatrial or biventricular pacing.) The second letterrefers to which chambers are sensed by the pacemaker's sensing channelsand uses the same letter designations as used for pacing. The thirdletter refers to the pacemaker's response to a sensed P wave from theatrium or an R wave from the ventricle and may be an I (for inhibited),T (for triggered), D (for dual in which both triggering and inhibitionare used), and O (for no response). Additional sensing of physiologicaldata allows some pacemakers to change the rate at which they pace theheart in accordance with some parameter correlated to metabolic demand.Such pacing is called rate-adaptive pacing and is designated by a fourthletter added to the three-letter code, R. Modern pacemakers aretypically programmable so that they can operate in any mode which thephysical configuration of the device will allow.

Pacemakers can enforce a minimum heart rate either asynchronously orsynchronously. In asynchronous pacing, the heart is paced at a fixedrate irrespective of intrinsic cardiac activity. There is thus a riskwith asynchronous pacing that a pacing pulse will be deliveredcoincident with an intrinsic beat and during the heart's vulnerableperiod which may cause fibrillation. Most pacemakers for treatingbradycardia or delivering CRT today are therefore programmed to operatesynchronously in a so-called demand mode where sensed cardiac eventsoccurring within a defined interval either trigger or inhibit a pacingpulse. Inhibited demand pacing modes utilize escape intervals to controlpacing in accordance with sensed intrinsic activity. In an inhibiteddemand mode, a pacing pulse is delivered to a heart chamber during acardiac cycle only after expiration of a defined escape interval duringwhich no intrinsic beat by the chamber is detected. If an intrinsic beatoccurs during this interval, the heart is thus allowed to “escape” frompacing by the pacemaker. Such an escape interval can be defined for eachpaced chamber. For example, a ventricular escape interval can be definedbetween ventricular events so as to be restarted with each ventricularsense or pace. The inverse of this escape interval is the minimum rateat which the pacemaker will allow the ventricles to beat, sometimesreferred to as the lower rate limit (LRL).

During normal physiological beats, atrial contractions augment thediastolic filling of the ventricles. When the ventricles are paced uponexpiration of a ventricular escape without regard to atrial activitysuch as in a VVI mode, the normal synchrony between atrial andventricular contractions that occurs in intrinsic physiological beats islost. Such atrio-ventricular dyssynchrony can compromise cardiac outputto a clinically significant extent, sometimes referred to as pacemakersyndrome. It is therefore normally preferable to employ atrial triggeredpacing modes that attempt to maintain the physiological synchronybetween atrial and ventricular contractions.

In atrial triggered modes (e.g., VDD and DDD modes), another ventricularescape interval is defined between atrial and ventricular events,referred to as the atrio-ventricular delay interval or AVD. Theatrio-ventricular interval is triggered by an atrial sense or pace andstopped by a ventricular sense or pace. A ventricular pacing pulse isdelivered upon expiration of the atrio-ventricular interval if noventricular sense occurs before. The value of the atrio-ventricularinterval for optimal preloading of the ventricles will vary with heartrate and in a manner that differs from patient to patient. If a patienthas a physiologically normal atrial rhythm, ventricular pacing triggeredby atrial senses also allows the ventricular pacing rate to beresponsive to the metabolic needs of the body. If the atrial rhythm istoo slow, the device can be configured to pace the atria on an inhibiteddemand basis such as in DDD mode which may include rate-adaptive pacing.An atrial escape interval is then defined as the maximum time intervalin which an atrial sense must be detected after a ventricular sense orstimulus before an atrial stimulus will be delivered. The lower ratelimit interval is then the sum of the atrial escape interval and theatrio-ventricular interval.

In a patient with normal AV conduction (i.e., no degree of AV block) andnormal ventricular function, the optimum AVD that maximizes cardiacoutput will usually correspond closely with the intrinsicatrio-ventricular interval. When such an AVD is used for bradycardiapacing of the ventricles, the ventricular pace is thus delivered closeto the time that the ventricles become excited due to intrinsic AVconduction. Similarly, an optimum AVD for resynchronizing the ventricleswith biventricular pacing in a patient with intact AV conduction willusually involve pre-exciting the ventricle having the conduction deficitwith an AVD that causes that ventricle to contract at roughly the sametime that the contralateral ventricle contracts due to intrinsic AVconduction. As described below, however, in patients with compromisedventricular function, it may be advantageous at times to employ an AVDfor ventricular pacing that is much shorter than the intrinsicatrio-ventricular interval.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the physical configuration of an exemplary pacingdevice.

FIG. 2 shows the components of an exemplary device.

FIG. 3 is a block diagram of the electronic circuitry of an exemplarydevice.

FIG. 4 illustrates a Starling curve that relates ventricular preload tocardiac output.

FIG. 5 illustrates the effects of reducing ventricular preload on aorticreflections.

FIG. 6 illustrates an exemplary algorithm for controlling entry and exitinto the AVDR mode.

DETAILED DESCRIPTION

As described below, an implantable pacing device for deliveringventricular pacing may be configured to intermittently reduce the AVDinterval for beneficial effect in patients with compromised ventricularfunction (e.g., HF patients and post-MI patients). The AVD interval maybe reduced, referred to herein as an AVD reduction or AVDR mode, byshortening the AVD in an atrial triggered ventricular pacing mode or byswitching to a non-atrial triggered ventricular pacing mode (e.g., VVI)and delivering paces at a rate above the intrinsic rate. Reduction ofthe AVD primarily results in two things: a reduction in the extent ofventricular pre-loading by the atria and a relatively asynchronousventricular contraction brought about by the ventricles being excitedfrom one or more ventricular pacing sites with little or no accompanyingventricular excitation via intrinsic AV conduction. The physiologicaleffects of AVD reduction may be either positive or negative on cardiacoutput, depending upon the individual patient.

Some patients may exhibit either an increased or relatively unchangedcardiac output when the AVD is reduced. Such patients, who may bereferred to as positive responders, include HF patients who areover-compensated with an increased ventricular preload. If the AVD iseither eliminated or severely reduced in these patients, the ventriclesthen receive very little preloading from the atria. The reduction inventricular pre-load may then actually improve ventricular function andincrease cardiac output. Another group of positive responders includepatients who exhibit an increased ventricular pressure afterload fromaortic pressure reflections due to atherosclerotic stiffening of theaorta. In these patients, the ventricles are subjected to an increasedstress and energy expenditure that does not contribute to increasingcardiac output. Reduction of the atrial preload by reducing oreliminating the AVD has been found to reduce the aortic pressurereflections in these patients and result in either an increased orrelatively unchanged cardiac output. Delivery of ventricular pacing inan AVDR mode to positive responders thus increases cardiac output and/orreduces ventricular wall stress and energy expenditure during systolewithout unduly compromising cardiac output. The AVDR mode may becontrolled by feedback to prevent the pulmonary congestion that mayoccur as blood is forced back into the lungs when atrial preloading isreduced. Such feedback may be provided by a sensor for detectingpulmonary edema, by sensor for measuring pulmonary artery pressure, orby a switch that may be actuated by the patient when symptoms ofpulmonary edema are present. The AVDR mode may also be controlled so asto be ceased or reduced in frequency when the patient is in a supineposition as detected by a posture sensor.

Another group of patients, referred to as negative responders, respondto AVD reduction with a relatively compromised cardiac output due to thereduction in atrial preloading and/or the relatively asynchronous andinefficient ventricular contraction resulting from a pace withoutintrinsic excitation from AV conduction. It has long been known that theheart muscle responds favorably to exercise so as to result in greaterpumping efficacy. Studies have shown that HF and post-MI patients canimprove their cardiac function and prognosis with regular periods ofexercise. Many HF and post-MI patients, however, are either debilitatedand cannot exercise or do not tolerate exercise well enough to exerciseeffectively. Delivering ventricular pacing with a reduced AVD to anegatively responding patient produces a relatively asynchronous andinefficient contraction that simulates the stress effects of exercise onthe heart. The optimum value of a shortened AVD for producing anasynchronous contraction may vary from patient to patient but wouldtypically be between 35-80 percent of the intrinsic atrio-ventricularinterval. A particular patient could also be both a positive or negativeresponder depending upon the extent to which the AVD is reduced.

Ventricular pacing in an AVDR mode may delivered on an intermittentbasis as controlled by specified entry and exit conditions that couldinclude lapsed time intervals, detection of pulmonary edema, exertionlevel (e.g., as measured by intrinsic heart rate, activity level, orminute ventilation), patient posture, cardiac output, and bloodpressure. The manner in which entry and exit into the AVDR mode iscontrolled will depend upon whether the effect of the AVDR mode is toimprove cardiac function in a positive responder (by increasing cardiacoutput and/or cardiac efficiency) or to simulate the effects of exercisein a negative responder. Also, the manner in which the AVDR mode isimplemented may depend upon whether the intended effect is to improvecardiac function or to simulate exercise. For example, cardiac functionmay be optimally improved in a positive responder by drasticallyshortening or even eliminating the AVD during ventricular pacing.Simulating exercise in a negative responder, on the other hand, may bebest accomplished with an AVD reduced to such an extent thatasynchronous contractions are produced but without severely reducingatrial preloading (e.g., with an AVD that is between 35-80 percent ofthe intrinsic atrio-ventricular interval). A more detailed descriptionof these techniques is given below after a description of an exemplarycardiac device.

1. Exemplary Cardiac Device

FIG. 1 shows an implantable cardiac device 100 for delivering pacingtherapy. Implantable pacing devices are typically placed subcutaneouslyor submuscularly in a patient's chest with leads threaded intravenouslyinto the heart to connect the device to electrodes disposed within aheart chamber that are used for sensing and/or pacing of the chamber.Electrodes may also be positioned on the epicardium by various means. Aprogrammable electronic controller causes the pacing pulses to be outputin response to lapsed time intervals and/or sensed electrical activity(i.e., intrinsic heart beats not as a result of a pacing pulse). Thedevice senses intrinsic cardiac electrical activity through one or moresensing channels, each of which incorporates one or more of theelectrodes. In order to excite myocardial tissue in the absence of anintrinsic beat, pacing pulses with energy above a certain threshold aredelivered to one or more pacing sites through one or more pacingchannels, each of which incorporates one or more of the electrodes. FIG.1 shows the exemplary device having two leads 200 and 300, each of whichis a multi-polar (i.e., multi-electrode) lead having electrodes 201-203and 301-303, respectively. The electrodes 201-203 are disposed in theright ventricle in order to excite or sense right ventricular or septalregions, while the electrodes 301-303 are disposed in the coronary sinusin order to excite or sense regions of the left ventricle. Otherembodiments may use any number of electrodes in the form of unipolarand/or multi-polar leads in order to excite different myocardial sites.As explained below, once the device and leads are implanted, the pacingand/or sensing channels of the device may be configured with selectedones of the multiple electrodes in order to selectively pace or sense aparticular myocardial site(s).

FIG. 2 shows the components of the implantable device 100 in moredetail. The implantable device 100 includes a hermetically sealedhousing 130 that is placed subcutaneously or submuscularly in apatient's chest. The housing 130 may be formed from a conductive metal,such as titanium, and may serve as an electrode for deliveringelectrical stimulation or sensing in a unipolar configuration. A header140, which may be formed of an insulating material, is mounted on thehousing 130 for receiving leads 200 and 300 which may be thenelectrically connected to pulse generation circuitry and/or sensingcircuitry. Contained within the housing 130 is the electronic circuitry132 for providing the functionality to the device as described hereinwhich may include a power supply, sensing circuitry, pulse generationcircuitry, a programmable electronic controller for controlling theoperation of the device, and a telemetry transceiver capable ofcommunicating with an external programmer or a remote monitoring device.

FIG. 3 shows a system diagram of the electronic circuitry 132. A battery22 supplies power to the circuitry. The controller 10 controls theoverall operation of the device in accordance with programmedinstructions and/or circuit configurations. The controller may beimplemented as a microprocessor-based controller and include amicroprocessor and memory for data and program storage, implemented withdedicated hardware components such as ASICs (e.g., finite statemachines), or implemented as a combination thereof. The controller alsoincludes timing circuitry such as external clocks for implementingtimers used to measure lapsed intervals and schedule events. As the termis used herein, the programming of the controller refers to either codeexecuted by a microprocessor or to specific configurations of hardwarecomponents for performing particular functions. Interfaced to thecontroller are sensing circuitry 30 and pulse generation circuitry 20 bywhich the controller interprets sensing signals and controls thedelivery of paces in accordance with a pacing mode. The controller iscapable of operating the device in a number of programmed pacing modeswhich define how pulses are output in response to sensed events andexpiration of time intervals. The controller also implements timersderived from external clock signals in order to keep track of time andimplement real-time operations such as scheduled AVDR mode pacing.

The sensing circuitry 30 receives atrial and/or ventricular electrogramsignals from sensing electrodes and includes sensing amplifiers,analog-to-digital converters for digitizing sensing signal inputs fromthe sensing amplifiers, and registers that can be written to foradjusting the gain and threshold values of the sensing amplifiers. Thesensing circuitry of the pacemaker detects a chamber sense, either anatrial sense or ventricular sense, when an electrogram signal (i.e., avoltage sensed by an electrode representing cardiac electrical activity)generated by a particular channel exceeds a specified detectionthreshold. Pacing algorithms used in particular pacing modes employ suchsenses to trigger or inhibit pacing, and the intrinsic atrial and/orventricular rates can be detected by measuring the time intervalsbetween atrial and ventricular senses, respectively.

The pulse generation circuitry 20 delivers pacing pulses to pacingelectrodes disposed in the heart and includes capacitive discharge orcurrent source pulse generators, registers for controlling the pulsegenerators, and registers for adjusting pacing parameters such as pulseenergy (e.g., pulse amplitude and width). The device allows adjustmentof the pacing pulse energy in order to ensure capture of myocardialtissue (i.e., initiating of a propagating action potential) by a pacingpulse. The pulse generation circuitry may also include a shocking pulsegenerator for delivering a defibrillation/cardioversion shock via ashock electrode upon detection of a tachyarrhythmia.

A telemetry transceiver 80 is interfaced to the controller which enablesthe controller to communicate with an external device such as anexternal programmer and/or a remote monitoring unit. An externalprogrammer is a computerized device with an associated display and inputmeans that can interrogate the pacemaker and receive stored data as wellas directly adjust the operating parameters of the pacemaker. Theexternal device may also be a remote monitoring unit that may beinterfaced to a patient management network enabling the implantabledevice to transmit data and alarm messages to clinical personnel overthe network as well as be programmed remotely. The network connectionbetween the external device and the patient management network may beimplemented by, for example, an internet connection, over a phone line,or via a cellular wireless link. A switch 24 is also shown as interfacedto the controller in this embodiment to allow the patient to signalcertain conditions or events to the implantable device. In differentembodiments, the switch 24 may be actuated magnetically, tactilely, orvia telemetry such as by a hand-held communicator. The controller may beprogrammed to use actuation of the switch 24 to control the delivery ofAVDR mode pacing.

A pacing channel is made up of a pulse generator connected to anelectrode, while a sensing channel is made up of a sense amplifierconnected to an electrode. Shown in the figure are electrodes 40 ₁through 40 _(N) where N is some integer. The electrodes may be on thesame or different leads and are electrically connected to a MOS switchmatrix 70. The switch matrix 70 is controlled by the controller and isused to switch selected electrodes to the input of a sense amplifier orto the output of a pulse generator in order to configure a sensing orpacing channel, respectively. The device may be equipped with any numberof pulse generators, amplifiers, and electrodes that may be combinedarbitrarily to form sensing or pacing channels. The device is thereforecapable of delivering single-site or multiple site ventricular pacingfor purposes of exercise simulation as well as conventional pacing. Oneor more pacing channels may also be configured, by appropriate leadplacement and pulse energy/frequency settings, for delivering electricalstimulation to stimulate sympathetic and/or parasympathetic nerves. Forexample, a lead with a stimulation electrode may be placed in proximityto the vagus nerve in order to stimulate that nerve and increaseparasympathetic activity. The switch matrix 70 also allows selected onesof the available implanted electrodes to be incorporated into sensingand/or pacing channels in either unipolar or bipolar configurations. Abipolar sensing or pacing configuration refers to the sensing of apotential or output of a pacing pulse between two closely spacedelectrodes, where the two electrodes are usually on the same lead (e.g.,a ring and tip electrode of a bipolar lead or two selected electrodes ofa multi-polar lead). A unipolar sensing or pacing configuration is wherethe potential sensed or the pacing pulse output by an electrode isreferenced to the conductive device housing or another distantelectrode.

The device may also include one or more physiological sensing modalitiesfor use in controlling pacing and/or the initiation/cessation of theAVDR mode. An accelerometer 26 enables the controller to adapt thepacing rate in accordance with changes in the patient's physicalactivity. In order to detect patient posture for purposes of controllingAVDR mode pacing, the accelerometer 26 may be a multi-axisaccelerometer. An impedance sensor 25 may be configured with electrodesfor measuring minute ventilation for use in rate adaptive pacing and/orcardiac output for use in controlling the AVDR mode. The impedancesensor 25 may also be configured to detect pulmonary edema bymeasurement of trans-pulmonary impedance. The device may also include apressure sensor that may be used, for example, to measure pressure inthe pulmonary artery.

2. Reduction of AVD to Improve Cardiac Function

Inadequate pumping of blood into the arterial system by the heart issometimes referred to as “forward failure,” with “backward failure”referring to the resulting elevated pressures in the lungs and systemicveins which lead to congestion. Backward failure is the naturalconsequence of forward failure as blood in the pulmonary and venoussystems fails to be pumped out. Forward failure can be caused byimpaired contractility of the ventricles due, for example, to coronaryartery disease, or by an increased afterload (i.e., the forces resistingejection of blood) due to, for example, systemic hypertension orvalvular dysfunction. One physiological compensatory mechanism that actsto increase cardiac output in this situation is due to backward failurewhich increases the diastolic filling pressure of the ventricles andthereby increases the preload (i.e., the degree to which the ventriclesare stretched by the volume of blood in the ventricles at the end ofdiastole). An increase in preload causes an increase in stroke volumeduring systole, a phenomena known as the Frank-Starling principle,whereby increases in myocardial fiber lengthening during diastoleresults in greater contractile force being generated during systole.Thus, heart failure can be at least partially compensated by thismechanism but at the expense of possible pulmonary and/or systemiccongestion.

Compensation of heart failure by increasing ventricular preload is onlyeffective in increasing cardiac output up to a certain extent, however,beyond which an increased preload may actually diminish cardiac output.FIG. 4 illustrates this situation by showing examples of two Starlingcurves, one for a normal subject and the other for an HF patient, thatrelate cardiac output to ventricular preload. Both curves show apositively sloping region where cardiac output increases with increasingpreload and a negatively sloping region where further increases inpreload cause a decrease in cardiac output. At the point labeled C onthe normal curve, a normal or adequate cardiac output results from aparticular amount of preload. At that same preload for an HF patient,however, an inadequate cardiac output results, shown as point A on theHF curve. This situation may be compensated for by increasing thepreload to increase cardiac output to an adequate level, shown as pointB on the HF curve. Any further increases in preload, however, moves tonegatively sloping region of the Starling curve labeled D and causes adiminution in cardiac output. HF patients who are operating in anegatively sloping region of their Starling curve may be said to beovercompensated, and such patients may be identified by clinicalhemodynamic testing. The cardiac function of these patients may beimproved by reducing or eliminating the contribution of atrialcontractions to ventricular preload with AVDR pacing.

Another situation in which the atrial contribution to ventricularpreload may be deleterious is when aortic reflections, secondary toarterial stiffening from atherosclerosis, occur. In this case theventricle is also unnecessarily loaded with additional pressure, with nobenefit in forward flow. The additional pressure caused by thesereflections is not of an insignificant magnitude (e.g., 3 to 15 mmHg).This problem of mechanical-impedance mismatch between the pump and itsload, a product of normal aging and genetic disposition to endothelialdisease, has been well described in the literature as a precursor tohypertension and heart failure. The mechanism of reflections involvesthe reduced capacitance of the arterial load, a result of a stifferaorta and arterial tree. It has been found that these aortic reflectionsbe significantly reduced by ventricular pacing with short AV delays asillustrated by FIG. 5 for an example patient. In FIG. 5, three pressurechannels are shown: aortic pressure AOP, left ventricular pressure LVP,and the rate of left ventricular pressure change LV dP/dt. The patientshows aortic reflections, evident as “humps” labeled H in the top of theAOP pulse signal. The dP/dt signal also shows the reflection'sinflection point clearly, as small humps after the main systolic phaselabeled as INF. It is seen that when pacing with a short AVD isinitiated at point P, the aortic reflections evident in the AOP anddP/dt channels are reduced significantly. Such aortic reflections arewasteful, and eliminating them causes no loss in output, but does resultin less loading and more efficient pumping by the ventricle. Note alsothat the maximum value of dP/dt is unaffected. Thus, in thispathological condition, an implantable pacing device could intervenetherapeutically in patients identified with vascular stiffening toreduce the loading of the ventricle by pacing in an AVDR mode with ashort AVD to eliminate the needless reflections.

Patients identified as either overcompensated with either high diastolicfilling pressures or as having aortic reflections may thus be regardedas positive responders to AVDR pacing. That is, AVDR pacing in thesepatients results in improved cardiac function manifested as increasedcardiac output and/or cardiac pumping efficiency. AVDR pacing reduces oreliminates the atrial contribution to ventricular preload, implementedeither by pacing with a very short or zero AV delay, or by pacing in aVVI mode just above the normal sinus rate. It is well known, however,that AV dissociation in dual chamber pacing can cause lung edema and theso called “pacemaker syndrome” malaise. The reason for this additionalcongestion is the backing of atrial pressure into the lungs, when theatria contract against a closed mitral valve. AVDR pacing, byeliminating AV synchrony, may have the same risk. Certain HF patientswith good lymphatics, however, may be relatively immune to this risk,much in the same way that some HF patients do very well despite highwedge pressures. In these patients, AVDR pacing may be delivered by animplantable device on a more or less chronic basis. In patients who donot tolerate AV dyssynchrony well, on the other hand AVDR pacing therapymay be delivered intermittently with some sort of closed loop feedbackcontrol of the AVDR mode. Such feedback control may be provided by asensor incorporated into the pacing device for pulmonary congestiondetection (e.g. by measuring thoracic impedance or pulmonary arterypressure) or may be provided by a patient-operated hand-held device orother type of switch that the patient would operate to turn on or offthe AVDR mode in accordance their own subjective symptoms. A posturalsensor control could also be included so that the AVDR mode would bedecreased in extent and/or frequency when the patient is determined tobe in a supine position which is more likely to cause edema. Feedbackcontrol could also be used to increase the extent and/or frequency ofthe AVDR mode when it is determined that increased cardiac output ismost needed such as during periods of exertion as determined fromactivity level, minute ventilation, or intrinsic heart rate.

3. Reduction of AVD to Simulate Exercise

Clinical studies have shown that HF and post-MI patients who follow aregular (e.g. 20 min/day, 3 times a week) exercise regimen havesymptomatic improvement compared to those who are sedentary. However,not all HF and post-MI patients can exercise due to their cardiacdisease or other debilitating conditions. As explained below, pacingtherapy may be designed to mimic exercise in order to provide protectionfrom heart failure development and/or attenuation/reversal of cardiacdisease progression.

When cardiac output is insufficient to meet the increased metabolicdemand, the body responds to the situation with increased activity ofthe sympathetic nervous system that, among other things, increases heartrate, myocardial contractility, and blood volume. Although acutelybeneficial, the long-term effects of increased sympathetic activity aredeleterious and lead to ventricular remodeling such as described above.A characteristic feature of chronic cardiac disease is an abnormalautonomic tone with an attenuated level of parasympathetic activityrelative to sympathetic activity. When the heart is stressed on aperiodic short-term basis, however, such as occurs with regularexercise, the effect is beneficial on both myocardial function andautonomic tone, leading to an increased level of parasympatheticactivity. In order to mimic the effects of exercise, pacing therapy canbe delivered on a short-term basis in a manner that stresses the heartsimilar to exercise. Such pacing therapy is referred to herein assimulated exercise pacing. Simulated exercise pacing may generallyinvolve pacing the heart in a manner that temporarily compromisescardiac output by producing relatively inefficient ventricularcontractions and/or some degree of atrio-ventricular dyssynchrony suchas described in co-pending U.S. patent application Ser. No. 11/559,131,filed on Nov. 13, 2006.

One way of delivering simulated exercise pacing is with an AVDR mode. Asdescribed earlier, reducing the AVD causes AV dyssynchrony thatdecreases the amount of ventricular preloading. In a negative responder,decreasing the ventricular preload decreases cardiac output, and thebody may respond to this decrease in a manner similar to its response toexercise. Ventricular pacing with a reduced AVD also causes a relativelyasynchronous contraction that can decrease cardiac output to mimic theeffects of exercise. The mechanism behind this effect is that when theventricles are stimulated to contract by a pacing pulse applied throughan electrode located at a particular pacing site, the excitation spreadsfrom the pacing site by conduction through the myocardium. This isdifferent from the normal physiological situation, where the spread ofexcitation to the ventricles from the AV node makes use of the heart'sspecialized conduction system made up of Purkinje fibers which allows arapid and synchronous excitation of the entire ventricular myocardium.The excitation resulting from a pacing pulse, on the other hand,produces a relatively asynchronous contraction due to the slowervelocity at which the excitation is conducted from the pacing site tothe rest of the myocardium. Regions of the myocardium located moredistally from the pacing site are also excited later than regionsproximal to the pacing site as compared with an intrinsic contractionand subjected to increased mechanical stress. This increased regionalstress may elicit cellular changes in the myocardium similar to thosecaused by stress due to exercise.

As described above, AVDR pacing can be delivered to the heart in a waythat mimics the beneficial effects of exercise. Chronic simulatedexercise pacing, however, could overstress the heart in HF or post-MIpatients and could be hazardous. Accordingly, it would ordinarily bepreferable to deliver simulated exercise pacing on an intermittentbasis. As described below, a pacing device may therefore be configuredto switch from a normal operating mode to an AVDR mode according to somedefined exit and entry conditions that cause intermittent operation inthe AVDR mode. Such entry and exit conditions, for example, may define aschedule that specifies switching in response to lapsed time intervalsand/or in response to one or more other types of conditions detectableby the device.

4. Implementation of Normal and AVDR Modes

Switching from a normal operating mode to the AVDR mode may beimplemented in a number of ways. If the normal mode does not includedelivery of pacing therapy, the AVDR mode may include delivery ofventricular pacing in an atrial triggered mode with a short AVD ordelivery of ventricular pacing a non-atrial triggered mode (e.g., VVI)at a rate above the intrinsic rate. If the normal mode includes atrialtriggered pacing with a specified AVD, the AVDR mode may includeventricular pacing in an atrial triggered mode using an AVD shorter thanthat used in the normal operating mode or a non-atrial triggered modesuch as VVI. For purposes of specifying the AVD used in the AVDR mode,the device may be configured to measure the intrinsic atrio-ventricularinterval and compute the AVD as a specified percentage thereof. Thedevice may also be configured to measure the intrinsic sinus rate beforeswitching to non-atrial triggered ventricular pacing in the AVDR modeand delivering pacing at some higher rate. Non-atrial triggered pacingin the AVDR mode may also be delivered in an overdrive pacing mode wherethe pacing rate is varied in a manner that attempts to avoid intrinsicbeats. When some kind of pacing therapy is delivered in the normaloperating mode and the device possesses multiple pacing channels withdifferent pacing sites, the AVDR mode may involve using either the sameor a different pacing channel for delivering ventricular pacing. TheAVDR mode may also involve ventricular pacing at multiple sites and/orswitching to different pacing sites during operation of the modeaccording to some defined schedule.

5. Conditional Entry and Exit Into AVDR Mode

The device may be configured to use one or more entry and/or exitconditions in controlling entry and/or exit into the AVDR. An entry orexit condition could be, for example, a lapsed time interval (e.g.,specified time(s) of the day), actuation of a switch by the patient(e.g., a magnetically or tactilely actuated switch interfaced to thedevice controller), a command received via telemetry, detection ornon-detection of a condition such as pulmonary edema or a supineposture, or a measured variable being within or out of a specifiedrange. Examples of such measured variables include heart rate, activitylevel, minute ventilation, cardiac output, heart sounds, and bloodpressure. Entry and/or exit conditions may also be composite conditionswhere a plurality of entry and/or exit conditions are logically ORed orANDed together to determine whether a composite entry or entry conditionis satisfied. FIG. 6 illustrates an exemplary algorithm executable bythe device controller for controlling entry and exit into the AVDR mode.In this example, one of the entry conditions is a specified time of theday during which it is desired to delivery AVDR pacing if other entryconditions are met. As shown in the figure, the controller of the deviceis programmed to transition through a number of different states,designated as A1 through A6. At state A1, the device operates in itsnormal operating mode. At state A2, while continuing to operate in stateA1, the device determines whether it should switch to the AVDR modebased upon a lapsed time interval or a triggering condition. Optionally,the device may also be configured to test for one or more particularentry conditions before switching to the simulated exercise mode asimplemented by state A3. Examples of entry conditions that must besatisfied before the switch to the AVDR mode include a measured exertionlevel being within a specified entry range (where exertion level may bemeasured by, e.g., heart rate, activity level, or minute ventilation),non-detection of cardiac arrhythmias, non-detection of cardiac ischemia,receipt of a telemetry command, and actuation by the patient of amagnetically or tactilely actuated switch incorporated into the devicethat allows switching to the AVDR mode. At state A3, the device checksto see if the one or more entry conditions are satisfied and returns tostate A1 if not. If the appropriate entry conditions are satisfied, thedevice switches to the AVDR mode at state A4. The AVDR mode supercedesthe normal operating mode to the extent necessary to carry out the AVDRpacing but may allow certain functions performed in the normal operatingmode to continue. Alternatively, the AVDR mode could be said toincorporate particular functions of the normal operating mode, whichfunctions are modified if necessary to deliver the AVDR pacing. Whileexecuting in the AVDR mode, the device may be configured to monitor forone or more exit conditions which cause the device to revert to thenormal operating mode. Such exit conditions could be the same ordifferent from the entry conditions that must be satisfied beforeentering the AVDR mode. At state A5, while executing in the AVDR mode,the device monitors for the occurrence of one or more exit conditionssuch as a measured exertion level being outside a specified permissiblerange, a measured heart rate being outside a specified permissiblerange, presence of a cardiac arrhythmia, presence of cardiac ischemia,receipt of a telemetry command, and actuation by the patient of amagnetically or tactilely actuated switch incorporated into the deviceby the patient to stop delivery of AVDR pacing. If an exit conditionoccurs, the device returns to the normal operating mode at state A1.Otherwise, the device proceeds to state A6 and checks to see if theprescribed amount and/or duration of AVDR pacing have been delivered. Ifthe specified amount or duration of AVDR pacing has been delivered, thedevice returns to state A1 and resumes the normal operating mode.Otherwise, the device loops back to state A5 to monitor for exitconditions.

The specification of particular entry and exit conditions for switchingto the AVDR mode will depend upon the response of the patient to theparticular kind of AVDR pacing being delivered. For example, in the caseof a positive response to the AVDR pacing so that cardiac function isimproved, the entry condition could be specified to be always satisfiedso that AVDR pacing is delivered continuously or could be lapsed timeinterval to deliver AVDR pacing periodically. An entry condition couldalso be a measured exertion level being above some specified value. Exitconditions could then be detection of pulmonary edema, detection of asupine posture, and/or receipt of a command to cease AVDR pacingreceived via telemetry or actuation of a switch. In the case of anegative response to the AVDR pacing that simulates exercise, the entrycondition(s) could be a lapsed time interval, measured cardiac outputbeing above some specified value, and/or measured exertion level beingbelow some specified value. For example, the device may be programmed todeliver AVDR pacing that simulates exercise for a prescribed amount oftime per day (e.g. 30 min). The time when therapy delivery is startedmay be random (once per day at a random time), at a specific time eachday, or triggered by a specific event (e.g. when the patient fallsasleep, the patient wakes up, or the patient's exertion level fallsbelow a certain threshold).

6. Exemplary Implementation Schemes

In an exemplary embodiment, the device is programmed to periodically(e.g., every 24 to 72 hours) switch to the AVDR mode for some specifiedperiod of time, referred to as the AVD reduction period or AVDRP (e.g.,15-60 minutes). If the device delivers some kind of therapy during itsnormal mode (e.g., for cardiac resynchronization therapy, remodelingcontrol therapy, or bradycardia), the AVDR mode could be implemented asatrial triggered ventricular pacing (e.g., VDD or DDD) with a shorter AVdelay than that used in the normal mode. If no pacing is delivered inthe normal mode, the AVDR mode could be implemented as atrial triggeredventricular pacing with a specified short AV delay. If the device isequipped with an atrial lead and only a single implanted ventricularlead, the implanted ventricular site would be paced with the reduced AVdelay for the entire AVDRP. If the device is equipped with electrodesimplanted at multiple ventricular sites (e.g., as multiple leads or asone or multi-polar leads), all or some selected subset of theventricular pacing sites could be paced during the AVDRP. Theventricular sites could also be rotated during the AVDRP according to aspecified duty cycle. For example, if the device has electrodesimplanted at two ventricular sites, the AVDR mode could be implementedas AVDR pacing delivered to a selected one of the sites for entireAVDRP, AVDR pacing delivered to one site for some percentage (e.g. 50%)of the AVDRP and switching to the other site for remaining portion ofthe AVDRP, or AVDR pacing delivered to both ventricular sites for eachpaced cycle (either simultaneously or with offset between the two sites)during the entire AVDRP. Similarly, if device has more than twoventricular leads or more than two ventricular pacing sites (e.g.quadripolar lead), AVDR pacing could be delivered to a single selectedsite for the entire AVDRP, AVDR pacing could be delivered to all of theimplanted sites for each paced cycle (either simultaneously or withspecified offsets) during the AVDRP, or AVDR pacing could be rotatedfrom one ventricular site to the next during the AVDRP. For example, ifthere are four ventricular pacing sites, AVDR pacing could be deliveredto a first site for the first 25% of the AVDRP, to a second site for thenext 25% of the AVDRP, etc., where the percentage of time each site ispaced may or may not be evenly distributed. Periodic switching to theAVDR mode may be started immediately following an incident event (e.g.an MI or heart failure decompensation), or the device may be programmedautomatically wait a certain period of time (e.g. 30 days post-MI) toinitiate the mode switching.

7. Other Embodiments

As described above, AVDR pacing may be used to simulate exercise byintentionally causing asynchronous ventricular contractions. Asdescribed in co-pending U.S. patent application Ser. No. 11/559,131,filed on Nov. 13, 2006. asynchronous contractions may also be producedin other ways such as by pacing different sites at different times tocause the heart to contract in an inefficient way, and the embodimentsdescribed herein may be combined with any of the embodiments describedin that application. Also, some patients may exhibit intrinsicasynchrony and therefore be treated with some kind of pacing therapythat results in more coordinated contractions (e.g., cardiacresynchronization therapy), and simulated exercise may be produced bysimply turning off such pacing for some period of time. For suchpatients, any of the embodiments described herein may be modified byreplacing the AVDR mode with a mode in which pacing is ceased andintrinsic contractions are allowed to occur.

U.S. patent application Ser. No. 11/561,049, filed on Nov. 17, 2006describes methods and apparatus for treating myocardial ischemia inwhich the stress experienced by a myocardial region identified asvulnerable to becoming ischemic is either mechanically loaded orunloaded with pre-excitation pacing. The embodiments described hereinfor pacing in an AVDR mode may be combined with any of the embodimentsdescribed in the Ser. No. 11/561,049 for loading or unloading avulnerable myocardial region.

The invention has been described in conjunction with the foregoingspecific embodiments. It should be appreciated that those embodimentsmay also be combined in any manner considered to be advantageous. Also,many alternatives, variations, and modifications will be apparent tothose of ordinary skill in the art. Other such alternatives, variations,and modifications are intended to fall within the scope of the followingappended claims.

1. A cardiac device, comprising: one or more ventricular pacing channelsfor delivering pacing pulses to one or more ventricular sites; acontroller programmed to operate the device in either a normal operatingmode or AV delay reduction (AVDR) mode; wherein, in the AVDR mode, thecontroller is programmed to deliver paces to the one or more ventricularsites using a pacing mode that decreases atrial preloading of theventricles as compared with the normal operating mode; and, wherein thecontroller is programmed to intermittently switch from the normaloperating mode to the AVDR mode according to a one or more specifiedentry conditions and switch from the AVDR mode to the normal operatingmode according to one or more specified exit conditions.
 2. The deviceof claim 1 wherein the AVDR mode includes pacing a ventricular siteusing a VVI pacing mode with a ventricular escape interval shorter thana patient's intrinsic heart rate.
 3. The device of claim 1 wherein theAVDR mode includes pacing a ventricular site using an atrial triggeredpacing mode with an AV delay interval shorter than a patient's intrinsicAV delay interval.
 4. The device of claim 1 wherein one or more of thespecified entry or exit conditions is a lapsed time interval to causeperiodic switching to the AVDR mode.
 5. The device of claim 1 furthercomprising means for measuring a patient's exertion level and whereinthe controller is programmed to operate in the AVDR mode only if themeasured exertion level is within a specified range.
 6. The device ofclaim 1 further comprising means for detecting pulmonary edema andwherein the controller is programmed to operate in the AVDR mode only ifpulmonary edema is not detected.
 7. The device of claim 1 furthercomprising means for detecting a patient's posture and wherein thecontroller is programmed to not operate in the AVDR mode only if thepatient is in a supine position.
 8. The device of claim 1 furthercomprising means for measuring pulmonary arterial pressure and whereinthe controller is programmed to operate in the AVDR mode only ifpulmonary arterial pressure is within a specified range.
 9. The deviceof claim 1 wherein one or more of the specified entry or exit conditionsis a command to enter or exit the AVDR mode received via telemetry or apatient-operated switch.
 10. The device of claim 1 wherein thecontroller is programmed to use different pacing channels in the AVDRmode than in the normal operating mode.
 11. The device of claim 1wherein the controller is programmed to deliver pacing through multipleventricular pacing channels for each paced cycle, either simultaneouslyor with one or more specified offsets, during the AVDR mode.
 12. Thedevice of claim 1 wherein the controller is programmed to deliver pacingthrough multiple ventricular pacing channels during the AVDR mode, wherethe multiple ventricular pacing channels are rotated according to adefined schedule.
 13. A method, comprising: delivering pacing pulses toone or more ventricular sites in either a normal operating mode or AVdelay reduction (AVDR) mode; wherein, in the AVDR mode, paces aredelivered to the one or more ventricular sites using a pacing mode thatdecreases atrial preloading of the ventricles as compared with thenormal operating mode; and, intermittently switching from the normaloperating mode to the AVDR mode according to a one or more specifiedentry conditions and switching from the AVDR mode to the normaloperating mode according to one or more specified exit conditions. 14.The method of claim 13 wherein the AVDR mode includes pacing aventricular site using a VVI pacing mode with a ventricular escapeinterval shorter than a patient's intrinsic heart rate.
 15. The methodof claim 13 wherein the AVDR mode includes pacing a ventricular siteusing an atrial triggered pacing mode with an AV delay interval shorterthan a patient's intrinsic AV delay interval.
 16. The method of claim 13wherein one or more of the specified entry or exit conditions is alapsed time interval to cause periodic switching to the AVDR mode. 17.The method of claim 13 further comprising measuring a patient's exertionlevel and operating in the AVDR mode only if the measured exertion levelis within a specified range.
 18. The method of claim 13 furthercomprising using different pacing channels in the AVDR mode than in thenormal operating mode.
 19. The method of claim 13 further comprisingdelivering pacing through multiple ventricular pacing channels for eachpaced cycle, either simultaneously or with one or more specifiedoffsets, during the AVDR mode.
 20. The method of claim 13 furthercomprising delivering pacing through multiple ventricular pacingchannels during the AVDR mode, where the multiple ventricular pacingchannels are rotated according to a defined schedule.